Liquid drug preparations

ABSTRACT

Liquid drug preparations characterized by containing fudostein and an acid together with a sweetener such as sugar alcohol, trehalose or a sweetener having a high degree of sweetness. These liquid drug preparations are fudostein-containing liquid drug preparations which are free from color change or sedimentation upon prolonged storage and can be easily taken.

TECHNICAL FIELD

[0001] The present invention relates to a liquid drug preparationcontaining fudostein and, more particularly, to a liquid drugpreparation that is free from color change and sedimentation duringstorage for a long period of time notwithstanding inclusion of fudosteinand can be advantageously used as an expectorant.

BACKGROUND ART

[0002] Fudostein is a nonproprietary name forS-(3-hydroxypropyl)-L-cysteine of the following formula (I) and isuseful as a drug exhibiting an expectorative effect (Examined JapanesePatent Publication No. 7-88352).

[0003] Patients of chronic bronchitis or bronchial asthma have fatrespiratory epithelium submucosal glands, secrete an increased amount ofepithelium mucus due to excessive formation of goblet cells, and sufferfrom expectoration difficulties due to excessive secretion of mucinduring sickness. For these reasons, these patients have subjectivesymptoms such as phlegm blocking the peripheral respiratory tract in thebreast and difficulty in ejecting phlegm in the central respiratorytract. Fudostein is highly useful as an expectorant, since the drug cansignificantly improve these symptoms at a clinical dose.

[0004] Conventionally, a solid preparation using a starch, for example,as a carrier has been known as a fudostein preparation (Japanese PatentApplication Laid-open No.11-35459). However, there has been no liquidfudostein preparation that can be easily taken by a patient of asthmaand the like due to a problem of stability.

[0005] The reason is because a fudostein solution exhibits change incolor and produces sedimentation over time. Although these phenomenahave no direct effect on the drug efficacy, the change in color andsedimentation cause anxiety among the patients orally taking the drugand remarkably decrease the commercial value of the drug. Sincefudostein has a peculiar taste that gives an unfavorable sensation upondosing, the fudostein is preferably made into a syrup preparation byadding a sweetener. However, sucrose and glucose commonly used for syruppreparations, if added to a fudostein syrup preparation, react withfudostein and darken the color of the solution. This phenomenon alsounduly impairs the commercial value.

[0006] Therefore, development of a fudostein-containing liquid drugpreparation free from color change and sedimentation during long-termstorage can be easily taken has been desired. An object of the presentinvention is to provide such a liquid drug preparation.

DISCLOSURE OF THE INVENTION

[0007] As a result of extensive studies on compositions of fudosteinliquid preparations and additives to such compositions to achieve theabove object, the inventors of the present invention have found thatfudostein is easily discolored in a neutral region, but changes coloronly with difficulty and does not have a problem of sedimentation in anacidic region. The inventors have further found that if sugar alcohol,trehalose, or a sweetener having a high degree of sweetness is used asthe sweetener, the problem of browning of the solution can be avoided.These findings have led to completion of the present invention.

[0008] Specifically, the present invention provides a liquid drugpreparation comprising fudostein and an acid.

[0009] The present invention also provides a liquid drug preparationcomprising sugar alcohol, trehalose, or a sweetener having a high degreeof sweetness as the sweetener.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] The liquid drug preparation of the present invention can beprepared by adding an acid to a solution of fudostein to provide asolution having an acidic pH according to a conventional method.

[0011] Although there are no specific limitations, the content offudostein contained as the effective component in the liquid drugpreparation of the present invention is about 1-20 wt/vol % (hereinafterindicated as “%”), preferably 2-10%, and still more preferably 4-8%.

[0012] Water is used as the solvent for dissolving fudostein.Optionally, other solvents such as dehydrated ethanol, ethanol,propylene glycol, concentrated glycerin, glycerol, glyceride,polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, Macrogol200, Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 4000, andLauromacrogol can be added.

[0013] As the acid added to the liquid drug preparation of the presentinvention, organic acids and inorganic acids can be given. As aninorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, andthe like can be used. As an organic acid, acetic acid, malic acid,citric acid, tartaric acid, lactic acid, fumaric acid, succinic acid,adipic acid, gluconic acid, glucono-d-lactone, and the like can be used.These acids may be used either individually or in combination of two ormore.

[0014] The liquid drug preparation of the present invention may have anacidic pH, if the above acid is added. The pH is preferably 5.0 or less,and more preferably 4.0-2.5.

[0015] Preferably, a sweetener such as sugar alcohol, trehalose, or asweetener having a high degree of sweetness can be further added to theliquid drug preparation of the present invention. As examples of thesugar alcohol that can be added, polyhydric alcohols with a chainstructure obtained by reducing the carbonyl group of aldose or ketoseand cyclic sugar alcohols can be given. Specific examples includepolyhydric alcohols with a chain structure having 3-11 carbon atoms suchas D-sorbitol, D-mannitol, xylytol, erythritol, D-arabitol, anddulcitol, and cyclic sugar alcohols such as maltitol, platinit (reducedpalatinose), xylose, inositol, and lactitol. Of these, D-sorbitol,D-mannitol, xylytol, and erythritol are preferable. As examples of thehigh sweetness sweetener, stevia, aspartame, thaumatin, sucralose,saccarin and its salt, and glycyrrhizic acid and its salt can be given.Of these, stevia, aspartame, saccarin, and sodium saccharin arepreferable. These sweeteners may be used either individually or incombination of two or more.

[0016] When the sugar alcohol or trehalose is used in the liquid drugpreparation of the present invention, the amount incorporated is 1-50%,preferably 5-40%, and more preferably 10-30%. If the sweetener with ahigh degree of sweetness is added, the amount added is 0.01-1.0%. Theaddition of the sweetener in an amount of this range masks the peculiartaste possessed by fudostein, while preventing browning of the solution.

[0017] Any optional components that are pharmaceutically acceptable canbe further added to the liquid drug preparation of the presentinvention. Such optional components include thickeners such as sodiumalginate, carboxyvinyl polymer, carmellose sodium, xanthan gum,crystalline cellulose.carmellose sodium, hydroxyethyl cellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, and polyvinylalcohol; preservatives such as sorbic acid or its salt, benzoic acid orits salt, parabenes (ethyl parahydroxybenzoate, methyl p-oxybenzoate,butyl p-oxybenzoate, propyl parahydroxybenzoate, etc.); colorants suchas natural colorants (caramel, β-carotene, etc.) and artificialcolorants (edible dyes, sodium riboflavin phosphate, etc.); and perfumessuch as orange oil, lemon oil, menthol, vanillin, fruit flavors(strawberry, pineapple, orange, apple, lemon, lime, grapefruit, etc.),crude drug flavors (herb, mint, etc.), beverage-type flavors (cocoa,tea, lemon soda, etc.), and confectionery-type flavors (chocolate,yoghurt, etc.).

[0018] The liquid drug preparation of the present invention made in theabove manner can be used as an oral expectorant and the like.

EXAMPLES

[0019] The present invention will be described in more detail by way ofexamples which should not be construed as limiting the presentinvention.

Example 1

[0020] Study of the influence of pH on fudostein liquid preparations:

[0021] Aqueous solutions containing 8 g of fudostein were adjusted to pH2-7 using an appropriate amount of phosphoric acid or sodium hydroxideas shown in Table 1. Purified water was added to make the total amountof each solution 100 ml, thereby obtaining liquid fudostein preparationswith different pHs. The liquid preparations were preserved at 70° C. forseven days to examine the residual ratio of fudostein in the solutions,color change, and sedimentation. The residual ratio of fudostein wascalculated from the amount of fudostein determined by quantitativeanalysis using HPLC. The color change and sedimentation were evaluatedby naked eye observation and rated according to the following standard.The results are shown in Table 1.

[0022] Evaluation standard for color change:

[0023] Rate: Evaluation results

[0024] (−): There was no color change in the liquid preparation.

[0025] (±): There was slight color change in the liquid preparation.

[0026] (+): There was color change in the liquid preparation.

[0027] (++): There was remarkable color change in the liquidpreparation.

[0028] Evaluation standard for sedimentation

[0029] Rate: Evaluation results

[0030] (−): No sedimentation was observed.

[0031] (±): Slight sedimentation was observed.

[0032] (+): Sedimentation was observed.

[0033] (Results) TABLE 1 pH 7.0 pH 6.0 pH 5.0 pH 4.0 pH 3.5 pH 3.0 pH2.5 pH 2.0 Analytical 99.4 100.4 100.1 101.1 100.3 100.7 100.0 99.9value Residual ratio (%) Color change ++ + ± − − − − − Sedimentation − −− − − − ± ±

[0034] As a result, the liquid fudostein preparation was confirmed toremain stable at pH 5.0 or less, particularly at a pH in the range of3.0-4.0. In addition, there was almost no change in the pH of eachsolution, i.e. the pH change after seven days was within an allowableerror range.

Example 2

[0035] Study of the type of pH adjuster for fudostein liquidpreparation:

[0036] Aqueous solutions containing 8 g of fudostein were adjusted to pH3.5 by adding various acids shown in Table 2. Purified water was addedto make the total amount of each solution 100 ml, thereby obtainingliquid fudostein preparations. The liquid preparations were preserved at70° C. for seven days to evaluate color change in the same manner as inExample 1. The results are shown in Table 2.

[0037] (Results) TABLE 2 Analytical value Residual ratio (%) Colorchange Hydrochloric acid 99.7 − Phosphoric acid 100.5 − Sulfuric acid100.3 − Acetic acid 101.2 − Malic acid 99.3 − Citric acid 100.7 −Tartaric acid 100.7 − Lactic acid 99.5 − Fumaric acid 98.8 −

[0038] As a result, both inorganic acids and organic acids wereconfirmed to be usable in the liquid drug preparation of the presentinvention. In addition, there was almost no change in the pH of eachsolution due to the addition of acids, i.e. the pH change after sevendays was within an allowable error range.

Example 3

[0039] Study of the type of sweetener for fudostein liquid preparation:

[0040] Aqueous solutions containing 8 g of fudostein and 20 g ofsweeteners shown in Table 3 were adjusted to pH 3.5 by adding phosphoricacid. Purified water was added to make the total amount of each solution100 ml, thereby obtaining liquid fudostein preparations. The liquidpreparations were preserved at 70° C. for seven days to evaluate colorchange in the same manner as in Example 1. The results are shown inTable 3.

[0041] (Results) TABLE 3 Analytical value Residual ratio (%) Colorchange Purified white sugar 90.5 ++ Glucose 78.8 ++ Fructose 90.7 ++Isomerized sugar 90.8 ++ D-sorbitol 100.7 − D-mannitol 99.3 − Xylytol100.3 − Erythritol 99.5 − Trehalose 100.2 − Reduced malt sugar syrup *99.9 −

[0042] As a result, the use of sugar alcohol or trehalose as a sweetenerwas confirmed to maintain a high residual ratio of fudostein and preventcolor change. In addition, there was almost no change in the pH of eachsolution due to the addition of the sweeteners, i.e. the pH change afterseven days was within an allowable error range.

Example 4

[0043] Study of the type of sweetener for fudostein liquid preparation:

[0044] Aqueous solutions containing 8 g of fudostein and 0.1-0.2 g ofsweeteners shown in Table 4 were adjusted to pH 3.5 by adding phosphoricacid. Purified water was added to make the total amount of each solution100 ml, thereby obtaining liquid fudostein preparations. The liquidpreparations were preserved at 70° C. for seven days to evaluate colorchange in the same manner as in Example 1. The results are shown inTable 4.

[0045] (Results) TABLE 4 Analytical value Amount (g) Residual ratio (%)Color change Stevia 0.2 100.4 − Aspartame, 0.2 99.1 − Sodium saccharin0.1 99.4 −

[0046] As a result, the use of sweeteners with a high degree ofsweetness was confirmed to maintain a high residual ratio of fudosteinand prevent color change.

Example 5

[0047] Study of the amount of sugar alcohol in fudostein liquidpreparation:

[0048] Aqueous solutions containing 8 g of fudostein and D-sorbitol inthe amounts shown in Table 5 were adjusted to pH 3.5 by addingphosphoric acid. Purified water was added to make the total amount ofeach solution 100 ml, thereby obtaining liquid fudostein preparations.The liquid preparations were preserved at 70° C. for seven days toevaluate the residual ratio, color change, and sedimentation in the samemanner as in Example 1. The results are shown in Table 5.

[0049] (Results) TABLE 5 Analytical value Residual ratio (%) Colorchange Sedimentation 0% 99.6 − − 10% 99.4 − − 20% 99.0 − − 30% 99.3 − −40% 99.9 ± + 50% 100.4 + +

[0050] As a result, liquid fudostein preparations with a sugar alcoholconcentration of 40% or less, particularly 30% or less, were confirmedto be stable stable. In addition, there was almost no change in the pHof each solution due to the D-sorbitol content, i.e. the pH change afterseven days was within an allowable error range.

Example 6

[0051] Fudostein-containing oral liquid drug preparation:

[0052] An oral liquid drug preparation with the following formulationwas prepared according to a conventional manner. The pH of the liquiddrug preparation was 3.7. Component) Amount (wt %) Fudostein 8 gD-sorbitol 15 g Caramel 100 mg Sodium benzoate 70 mg Malic acidAppropriate amount Perfume (yoghurt-type) 100 mg Purified water BalanceTotal amount 100 ml

[0053] The preparation was stable with no decrease in the fudosteincontent, no color change, and no sedimentation. The peculiar taste offudostein was masked by the addition of D-sorbitol and perfume.

Example 7

[0054] Fudostein-containing oral liquid drug preparation:

[0055] An oral liquid drug preparation with the following formulationwas prepared according to a conventional manner. The pH of the liquiddrug preparation was 3.7. Component Amount (wt %) Fudostein 8 gErythritol 20 g Caramel 100 mg Sodium benzoate 70 mg Phosphoric acidAppropriate amount Perfume (orange-type) 100 mg Purified water BalanceTotal amount 100 ml

[0056] The preparation was stable with no decrease in the fudosteincontent, no color change, and no sedimentation. The peculiar taste offudostein was masked by the addition of erythritol and perfume.

Example 8

[0057] Fudostein-containing oral liquid drug preparation:

[0058] An oral liquid drug preparation with the following formulationwas prepared according to a conventional manner. The pH of the liquiddrug preparation was 3.7. Component Amount (wt %) Fudostein 8 g Reducedmalt sugar syrup* 20 g Caramel 100 mg Sodium benzoate 70 mg Malic acidAppropriate amount Perfume (menthol-type) 100 mg Purified water BalanceTotal amount 100 ml

[0059] The preparation was stable with no decrease in the fudosteincontent, no color change, and no sedimentation. The peculiar taste offudostein was masked by the addition of reduced malt sugar syrup andperfume.

Example 9

[0060] Fudostein-containing oral liquid drug preparation:

[0061] An oral liquid drug preparation with the following formulationwas prepared according to a conventional manner. The pH of the liquiddrug preparation was 3.7. Component Amount (wt %) Fudostein 8 gTrehalose 20 g Caramel 100 mg Sodium benzoate 70 mg Phosphoric acidAppropriate amount Perfume (chocolate-type) 100 mg Purified waterBalance Total amount 100 ml

[0062] The preparation was stable with no decrease in the fudosteincontent, no color change, and no sedimentation. The peculiar taste offudostein was masked by the addition of trehalose and perfume.

Example 10

[0063] Fudostein-containing oral liquid drug preparation:

[0064] An oral liquid drug preparation with the following formulationwas prepared according to a conventional manner. The pH of the liquiddrug preparation was 3.7. Component Amount (wt %) Fudostein 8 g Stevia100 mg Caramel 100 mg Sodium benzoate 70 mg Malic acid Appropriateamount Perfume (strawberry-type) 100 mg Purified water Balance Totalamount 100 ml

[0065] The preparation was stable with no decrease in the fudosteincontent, no color change, and no sedimentation. The peculiar taste offudostein was masked by the addition of stevia and perfume.

INDUSTRIAL APPLICABILITY

[0066] The liquid drug preparation of the present invention is highlystable and free from color change and sedimentation during a longstorage period in spite of the inclusion of fudostein. In addition, theliquid drug preparation comprising sugar alcohol, trehalose, or asweetener having a high degree of sweetness as a sweetener masks thepeculiar taste of fudostein without causing a problem of browning of thesolution. The liquid drug preparation of the present invention istherefore has a high commercial value as a expectorant and the like asan oral liquid preparation that can be easily taken.

1. A liquid drug preparation comprising fudostein and an acid.
 2. Theliquid drug preparation according to claim 1, having a pH of 5.0 orless.
 3. The liquid drug preparation according to claim 1 or 2, furthercomprising sugar alcohol, trehalose, or a sweetener having a high degreeof sweetness as a sweetener.
 4. The liquid drug preparation according toclaim 3, wherein the sugar alcohol is D-sorbitol, D-mannitol, xylytol,or erythritol.
 5. The liquid drug preparation according to claim 3,wherein the sweetener having a high degree of sweetness is stevia,aspartame, saccarin, or sodium saccharin.
 6. The liquid drug preparationaccording to any one of claims 1-5, wherein the acid is one or moreacids selected from the group consisting of hydrochloric acid,phosphoric acid, sulfuric acid, malic acid, citric acid, tartaric acid,lactic acid, and fumaric acid.